Deletion of a conserved Gata2 enhancer impairs haemogenic endothelium programming and adult Zebrafish haematopoiesis

Gata2 is a key transcription factor required to generate Haematopoietic Stem and Progenitor Cells (HSPCs) from haemogenic endothelium (HE); misexpression of Gata2 leads to haematopoietic disorders. Here we deleted a conserved enhancer (i4 enhancer) driving pan-endothelial expression of the zebrafish...

Descripción completa

Detalles Bibliográficos
Autores principales: Dobrzycki, Tomasz, Mahony, Christopher B., Krecsmarik, Monika, Koyunlar, Cansu, Rispoli, Rossella, Peulen-Zink, Joke, Gussinklo, Kirsten, Fedlaoui, Bakhta, de Pater, Emma, Patient, Roger, Monteiro, Rui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018942/
https://www.ncbi.nlm.nih.gov/pubmed/32054973
http://dx.doi.org/10.1038/s42003-020-0798-3
_version_ 1783497418527997952
author Dobrzycki, Tomasz
Mahony, Christopher B.
Krecsmarik, Monika
Koyunlar, Cansu
Rispoli, Rossella
Peulen-Zink, Joke
Gussinklo, Kirsten
Fedlaoui, Bakhta
de Pater, Emma
Patient, Roger
Monteiro, Rui
author_facet Dobrzycki, Tomasz
Mahony, Christopher B.
Krecsmarik, Monika
Koyunlar, Cansu
Rispoli, Rossella
Peulen-Zink, Joke
Gussinklo, Kirsten
Fedlaoui, Bakhta
de Pater, Emma
Patient, Roger
Monteiro, Rui
author_sort Dobrzycki, Tomasz
collection PubMed
description Gata2 is a key transcription factor required to generate Haematopoietic Stem and Progenitor Cells (HSPCs) from haemogenic endothelium (HE); misexpression of Gata2 leads to haematopoietic disorders. Here we deleted a conserved enhancer (i4 enhancer) driving pan-endothelial expression of the zebrafish gata2a and showed that Gata2a is required for HE programming by regulating expression of runx1 and of the second Gata2 orthologue, gata2b. By 5 days, homozygous gata2a(Δi4/Δi4) larvae showed normal numbers of HSPCs, a recovery mediated by Notch signalling driving gata2b and runx1 expression in HE. However, gata2a(Δi4/Δi4) adults showed oedema, susceptibility to infections and marrow hypo-cellularity, consistent with bone marrow failure found in GATA2 deficiency syndromes. Thus, gata2a expression driven by the i4 enhancer is required for correct HE programming in embryos and maintenance of steady-state haematopoietic stem cell output in the adult. These enhancer mutants will be useful in exploring further the pathophysiology of GATA2-related deficiencies in vivo.
format Online
Article
Text
id pubmed-7018942
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-70189422020-03-03 Deletion of a conserved Gata2 enhancer impairs haemogenic endothelium programming and adult Zebrafish haematopoiesis Dobrzycki, Tomasz Mahony, Christopher B. Krecsmarik, Monika Koyunlar, Cansu Rispoli, Rossella Peulen-Zink, Joke Gussinklo, Kirsten Fedlaoui, Bakhta de Pater, Emma Patient, Roger Monteiro, Rui Commun Biol Article Gata2 is a key transcription factor required to generate Haematopoietic Stem and Progenitor Cells (HSPCs) from haemogenic endothelium (HE); misexpression of Gata2 leads to haematopoietic disorders. Here we deleted a conserved enhancer (i4 enhancer) driving pan-endothelial expression of the zebrafish gata2a and showed that Gata2a is required for HE programming by regulating expression of runx1 and of the second Gata2 orthologue, gata2b. By 5 days, homozygous gata2a(Δi4/Δi4) larvae showed normal numbers of HSPCs, a recovery mediated by Notch signalling driving gata2b and runx1 expression in HE. However, gata2a(Δi4/Δi4) adults showed oedema, susceptibility to infections and marrow hypo-cellularity, consistent with bone marrow failure found in GATA2 deficiency syndromes. Thus, gata2a expression driven by the i4 enhancer is required for correct HE programming in embryos and maintenance of steady-state haematopoietic stem cell output in the adult. These enhancer mutants will be useful in exploring further the pathophysiology of GATA2-related deficiencies in vivo. Nature Publishing Group UK 2020-02-13 /pmc/articles/PMC7018942/ /pubmed/32054973 http://dx.doi.org/10.1038/s42003-020-0798-3 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Dobrzycki, Tomasz
Mahony, Christopher B.
Krecsmarik, Monika
Koyunlar, Cansu
Rispoli, Rossella
Peulen-Zink, Joke
Gussinklo, Kirsten
Fedlaoui, Bakhta
de Pater, Emma
Patient, Roger
Monteiro, Rui
Deletion of a conserved Gata2 enhancer impairs haemogenic endothelium programming and adult Zebrafish haematopoiesis
title Deletion of a conserved Gata2 enhancer impairs haemogenic endothelium programming and adult Zebrafish haematopoiesis
title_full Deletion of a conserved Gata2 enhancer impairs haemogenic endothelium programming and adult Zebrafish haematopoiesis
title_fullStr Deletion of a conserved Gata2 enhancer impairs haemogenic endothelium programming and adult Zebrafish haematopoiesis
title_full_unstemmed Deletion of a conserved Gata2 enhancer impairs haemogenic endothelium programming and adult Zebrafish haematopoiesis
title_short Deletion of a conserved Gata2 enhancer impairs haemogenic endothelium programming and adult Zebrafish haematopoiesis
title_sort deletion of a conserved gata2 enhancer impairs haemogenic endothelium programming and adult zebrafish haematopoiesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018942/
https://www.ncbi.nlm.nih.gov/pubmed/32054973
http://dx.doi.org/10.1038/s42003-020-0798-3
work_keys_str_mv AT dobrzyckitomasz deletionofaconservedgata2enhancerimpairshaemogenicendotheliumprogrammingandadultzebrafishhaematopoiesis
AT mahonychristopherb deletionofaconservedgata2enhancerimpairshaemogenicendotheliumprogrammingandadultzebrafishhaematopoiesis
AT krecsmarikmonika deletionofaconservedgata2enhancerimpairshaemogenicendotheliumprogrammingandadultzebrafishhaematopoiesis
AT koyunlarcansu deletionofaconservedgata2enhancerimpairshaemogenicendotheliumprogrammingandadultzebrafishhaematopoiesis
AT rispolirossella deletionofaconservedgata2enhancerimpairshaemogenicendotheliumprogrammingandadultzebrafishhaematopoiesis
AT peulenzinkjoke deletionofaconservedgata2enhancerimpairshaemogenicendotheliumprogrammingandadultzebrafishhaematopoiesis
AT gussinklokirsten deletionofaconservedgata2enhancerimpairshaemogenicendotheliumprogrammingandadultzebrafishhaematopoiesis
AT fedlaouibakhta deletionofaconservedgata2enhancerimpairshaemogenicendotheliumprogrammingandadultzebrafishhaematopoiesis
AT depateremma deletionofaconservedgata2enhancerimpairshaemogenicendotheliumprogrammingandadultzebrafishhaematopoiesis
AT patientroger deletionofaconservedgata2enhancerimpairshaemogenicendotheliumprogrammingandadultzebrafishhaematopoiesis
AT monteirorui deletionofaconservedgata2enhancerimpairshaemogenicendotheliumprogrammingandadultzebrafishhaematopoiesis

Ejemplares similares